This PPG application has evolved from three presently active R01 grants, which this application intends to replace. Severe chronic pulmonary hypertension (PH) - in spite of intravenous prostacyclin (PGI2) treatment - remains an important and challenging clinical problem. Our four projects have been designed to investigate specific aspects of human PH including primary and neonatal pulmonary hypertension. We start with the concept that pulmonary arteries differ from systemic vessels in that their response to "stress" or "injury" is different. We further postulate that the adult lung circulation remodels with endothelial cell proliferation (Project 1), whereas the neonatal lung circulation remodels without endothelial cell proliferation (Project 2). Vascular endothelial growth factor (VEGF) and its receptor, KDR. are critically involved in the formation of plexiform lesions in adult PH whereas reduced VEGF/KDR signaling in the fetus leads to a vasculogenesis failure characterized by a muscularized, pruned vascular tree. Project 3 develops a prospectively designed new rodent model of endothelial cell-proliferative, severe PH that has been built on inhibition of the VEGF receptor KDP, and proposes that endothelial cell death selects for the emergence of resistant, proliferative endothelial cells at sites of high shear stress. We anticipate that this rat model will permit the systematic investigation of the interplay between altered vasoreactivity (vasoconstriction) and development of obliterative pulmonary vascular arteriopathy. The information gathered from this model will include lung tissue transcript information gathered using the microarray GeneChip technology and will be compared with the gene expression data obtained from human PPH and 2nd PH lungs (Project 1). The fact that endothelial cell proliferation in PPH is monoclonal encourages the search for gene mutations. One candidate mutated gene is the TGF-B-RII gene coding for the TGF-B-II receptor, which is involved in cell growth/death control. Lastly, a severe loss of prostacyclin receptor (PGII-R) expression in the resistance vessels of PPH lungs provides rationale and focus for the investigation of the role of PGI2 and its receptor in pulmonary vascular remodeling (Project 4). Vascular smooth muscle cells from genetically engineered mice (Lung-specific PGI2-synthase gene overexpression and PGI2-receptor knock-out) will be examined for PGI2-R-dependent and independent growth. We believe that this highly integrated program addresses central issues of the pathobiology of severe human pulmonary hypertension.